Ziprasidone: Did You Know?

Ziprasidone (Geodon; Pfizer) is a new atypical antipsychotic agent indicated for the treatment of schizophrenia (SeeTable 1). Ziprasidone is a combined serotonin and dopamine receptor antagonist and also has activity at the serotonin and dopamine transport or re-uptake sites. It is in the benzisothiazole class and has a similar structure and receptor affinities to risperidone. See Table 2 for the pharmacokinetics of ziprasidone.

Table 1: FDA-Approved Indications of Atypical Antipsychotics

Indication

Olanzapine
(Zyprexa®)

Quetiapine
(Seroquel®)

Risperidone
(Risperdal®)

Ziprasidone
(Geodon)

Acute agitation in
psychotic patients

X

X

Bipolar mania

X

Manifestations of
psychotic disorders

X

X

Schizophrenia

X

X

X

X

Table 2: Pharmacokinetics
of Ziprasidone

Peak
Levels

3
to 8 hours

Peak
Response

4
weeks

Oral
Bioavailability

59%

Protein
Bound

99%

Half-Life
(mean)

7
hours

Volume
of Distribution

2.3
L/kg

Ziprasidone should be used with caution in patients who have
had adverse events with prior use of an atypical antipsychotic,
central nervous system disorders, gastrointestinal disease,
hepatic or renal insufficiency, or are pregnant. Some warnings
associated with ziprasidone use include QTc prolongation,
neuroleptic malignant syndrome, and tardive dyskinesia. Since
QTc prolongation may occur with ziprasidone therapy, this
agent should not be used 1) with other medications that prolong
the QTc interval (e.g., quinidine, moxifloxacin, dofetilide,
pimozide, sotalol, thioridazine); 2) in patients with a known
history of QTc prolongation (including long QT syndrome);
and 3) in patients with a history of cardiac arrhythmias,
recent acute myocardial infarction, or with uncompensated
heart failure. Ziprasidone therapy should be discontinued
in patients with persistent QTc measurements >500msec.

A third complication with the use of ziprasidone may be tardive dyskinesia
(TD). TD is a syndrome of potentially irreversible, involuntary,
dyskinetic movements. Chronic administration of antipsychotic
medications can increase the risk of developing tardive dyskinesia.

Ziprasidone therapy is contraindicated 1) in patients with hypersensitivity
to any component of the agent, 2) in patients with medications
that prolong the QT interval, 3) in patients with a known
history of QT prolongation, 4) in patients with a recent acute
myocardial infarction, and 5) in patients with uncompensated
heart failure.

Ziprasidone is classified as a pregnancy-risk category C; hence, studies
in animals have revealed adverse effects on the fetus and
there are no studies in women or studies in animals and women
have yet to be performed. Also, there are no additional data
available regarding ziprasidone use during pregnancy.

Some of the adverse effects of ziprasidone include dyspepsia, constipation,
nausea, abdominal pain, dry mouth, sedation, headache, postural
hypotension, dizziness, insomnia, and rash. It is one of the
atypical antipsychotic agents not to be associated with weight
gain, making it unique in its class.

Some possible drug interactions that may occur with ziprasidone include
ketoconazole and cimetidine. Ziprasidone should not be administered
in combination with other centrally acting agents due to its
central nervous system effects. Ziprasidone may also enhance
the effects of some antihypertensive agents due to its potential
for inducing orthostatic hypotension, as well as antagonize
the effects of levodopa and dopamine agonists. And finally,
because of the risk of ziprasidone causing QTc prolongation,
it should not be administered with any medication that prolongs
the QT interval.

Ziprasidone is available as 20-, 40-, 60-, and 80-mg capsules. Therapy
should be initiated at a dose of 20 mg administered orally
twice daily with food. The dose may be increased based on
response up to 80 mg twice daily. Dosage adjustments should
occur at intervals of not less than 2 days. Patients should
be observed for improvement for several weeks before upward
dosage adjustment to ensure use of the lowest effective dose.
There is no dosage adjustment required for mild to moderate
renal or hepatic impairment or for the elderly. The cost of
ziprasidone is the same for all strengths: $234 for a one
month supply ($7.80 per day).

Even though there are warnings associated with ziprasidone due to its
potential to prolong the QT interval, it still has a place
in therapy. Ziprasidone may be most effective in patients
who are resistant to standard antipsychotic agents and patients
with therapy limiting extrapyramidal symptoms or other adverse
effects, such as weight gain and increased cholesterol. Ziprasidone
was recently added to the Cleveland Clinic Foundation Formulary
of Accepted Drugs, however, its use is restricted to the
Department of Psychiatry. Additionally, before ziprasidone
therapy is initiated at CCF, patients must have a baseline
EKG.